142-LB: First Non-sulfonylurea Type Inhibitors of SUR1 Showed Superior Efficacy over Sulfonylureas, and Reversed Sulfonylurea Failure

Abstract

Sulfonylureas (SUs) have been used widely for a long time as a diabetic drug since first discovered in 1942. Because of their good glucose lowering effect and low cost it had been drug of choice until recently. However, SUs are lack of the glycemic durability and lose their efficacy mostly within 1-2 years, resulting in a steady HbA1c rise to or above pretreatment levels. This, so called SU failure, has been the main reason for limiting their use in the clinic. Our efforts for overcoming the SU failure led to the discovery of de novo type sulfonylurea receptor 1 (SUR1) antagonists (e.g., Cpd7). To the best of our knowledge, this is the first report of non-SU type SUR1 antagonists with the superior efficacy to known SU drugs. Molecular modeling with a recently published cryogenic electron microscopy structure of KATP channel showed that Cpd7 occupies the SUR1 binding site in a totally different region from known SUs such as glimepiride with a higher docking score. We hoped that such differences in structure classes and binding patterns lead to improved phenotypic effects. In insulinoma Min6 and INS-1 cells, treating with Cpd7 increased calcium influx and triggered a superior insulin secretion to glimepiride. In mouse oral glucose tolerance test, cpd7 showed a highly effective blood glucose lowering effect at a 30 mg/kg dose. It is well known that chronic glibenclamide treatment in Min6 cells induces unresponsiveness to most of SU drugs. So far no other SUR1 antagonists have been found effective in SU resistance. But we found that Cpd7 overcomes the SU resistance induced by chronic treatment of glibenclamide in Min6 and InS-1 cells. Therefore, it becomes clear that our newly discovered non-SU type SUR1 antagonists can be used for solving the resistance problems caused by the existing SU drugs. We expect that our discovery will lead to the development of a new type of SU drug which gives an alternative treatment option to diabetic patients in the near future. Disclosure D. Lim: None. J. Park: Employee; Self; LG Chem. D. Kim: Employee; Self; LG Chem. H. Park: None. Y. Kim: None.